Incremental health care expenditures for non-Hodgkin lymphoma in comparison with other cancers: Analysis of national survey data

BACKGROUND: Non-Hodgkin lymphoma (NHL) is among the most common cancers in the United States, with an estimated annual incidence of more than 80,000 and a high survival rate. However, limited national data exist regarding the health care burden of NHL. OBJECTIVE: To evaluate the incremental health care expenditures among patients with NHL using the Medical Expenditure Panel Survey (MEPS) data compared with patients with other cancers. METHODS: This observational cross-sectional study included all patients with NHL (≥ 18 years) and all individuals diagnosed with other cancers from the MEPS 2014-2019. The components of health care expenditures included hospital inpatient care, office-based visits, outpatient care, emergency department, prescription medications, dental, home health, and other expenditures. Patients with NHL and those diagnosed with other cancers were identified from the full-year consolidated MEPS Household Component 2014-2019. Descriptive weighted analysis was used to compare the health care expenditure components between individuals with NHL and all other cancers. A 2-part model using probit and generalized linear models with a log link function was used to estimate the incremental increase in total health care expenditures for NHL compared with all other cancers. RESULTS: According to the MEPS, there were 0.74 million patients with NHL (95% CI = 0.62-0.86) and 27.91 million patients with other cancers (95% CI = 26.69-29.13) annually. Most of the patients with NHL were White (78.36%), male (60.67%), and older than 65 years (45.8%). The unadjusted analysis indicated a total annual expenditure of $21,698 (95% CI = $16,752-$26,645) for NHL, which was significantly higher than the annual expenditure for patients with other cancers ($15,029 [95% CI = $14,476-$15,582]). Most of the total health expenditure of both the NHL group and the other cancers group was distributed in 3 categories of hospital inpatient care (29.15% vs 26.29%), office-based visits (28.10% vs 25.08%), and prescription medications (19.03% vs 22.57%). Based on the 2-part model adjusted for all covariates, the annual health care expenditure for NHL was $7,284 (95% CI = $1,432-$13,135), higher than the expenditure of patients diagnosed with all other cancers. Among the health care expenditure components, the office-based visits were $2,641 higher for patients with NHL compared with the other cancers group (95% CI = $1,129-$4,153). CONCLUSIONS: The economic burden of NHL is higher compared with other cancers. Most of the NHL expenditures were attributable to hospital inpatient services and office-based visits. The study findings can inform value-based care considerations because of a better understanding of utilization and care patterns for NHL.

Non-Hodgkin lymphoma (NHL) is one of the most common cancers in the United States, accounting for about 4% of all cancers. 1 The American Cancer Society estimated a total of 81,560 new cases of lymphoma in 2021 in the United States, with 20,720 deaths during the same period. 1 Overall, the probability of men and women developing NHL in their lifetime is about 1 in 41 and 1 in 52, respectively. 1 The 5-year survival rate of lymphoma is 72%, but it varies widely for different types and stages of the disease, with a range from 57% to 96%. 2 Given its high incidence and survival rates, lymphoma can be characterized as a chronic disease alternating between symptom-free and exacerbation phases that can benefit from treatment. 3 NHL is the most common type of lymphoma, distinguished from other types of lymphoma based on the appearance of the tumor cells. 3 According to the National Cancer Institute guidelines, treatment for NHL depends on the type of cancer, the progression of the disease, and the current health status of the patient. 4 Effective treatment can prevent or treat problems such as infections, low blood cell counts, and other symptoms caused by lymphoma. When patients are asymptomatic, physicians may defer treatment until the disease symptoms are evident as the disease progresses. However, when treatment is deferred, patients may have different clinical courses. As a result, frequent and careful follow-up is required to start effective treatment when the clinical course of the disease accelerates. The indolent course of the disease may be prolonged for some patients, but it might be brief for others, leading to more aggressive types of NHL that necessitate immediate care, which might be either new monoclonal antibody (eg, rituximab), antineoplastic agents (eg, venetoclax), chemotherapy, radiation therapy, or bone marrow transplantation for the most aggressive cases. 4 The care and treatment patterns for NHL can have significant cost implications.
One study using the MarketScan data from 1999 to 2000 found monthly direct medical costs of $3,833-$5,871 for newly diagnosed patients with NHL with different severities. 5 Another study using 2006-2009 US Oncology's iKnowMed oncology-specific electronic medical record system evaluated the direct medical costs of the disease among 1,002 lymphoma patients. 6 They reported monthly total costs of $859 and $3,527 during the first 6 months after the initial lymphoma diagnosis and during the first 6 months after the date of disease progression, respectively. 6 Another study specifically focused on the economic benefit of rituximab therapy for approved hematological uses in the United States, using cancer registry incidence data from the Surveillance, Epidemiology, and End Results linked to Medicare data. 7 They found $8.92 billion in incremental direct medical costs for rituximab and $16.52 billion in economic gain for all approved hematological uses.
The higher overall 5-year survival rate in NHL 8 (73%) compared with other highly lethal cancers (pancreatic cancer: 11% 9 ; lung cancer: 26% 10 ; and ovarian cancer: 49% 11 ), in addition to the high cost of the disease among older adults, can have significant health care consequences. However, there are limited nationally representative data regarding health care expenditures for NHL. Further, there is a data gap regarding the comparative health care burden of NHL with other cancers. In this retrospective study, we examined the health care expenditure burden associated with NHL in the United States and compared the incremental burden with other cancers using the Medical Expenditure Panel Survey (MEPS) data from 2014 to 2019.

DATA SOURCE
The MEPS is a set of large-scale surveys of US families and individuals, their medical providers, and employers across the United States. MEPS is a complete source of data on the cost and use of health care and health insurance coverage; it is sponsored by the Agency for Healthcare Research and Quality and the National Center for Health Statistics, part of the Centers for Disease Control and Prevention. 12 14 Overall, MEPS provides comprehensive information on the frequency, type, and cost of health care services used. Researchers often use this data to evaluate health care utilization and cost in the United States and the different factors that may affect them. 12,13 HC data collection is based on a stratified, multistage, and disproportionate sampling with an overlapping panel design that allows continuous participation for up to 2 years. The MEPS provides the opportunity for researchers to conduct cross-sectional as well as longitudinal studies. 13,15 In this study, we used the HC and the MPC parts of the MEPS. The HC component provides the person-level CONCLUSIONS: The economic burden of NHL is higher compared with other cancers. Most of the NHL expenditures were attributable to hospital inpatient services and office-based visits. The study findings can inform value-based care considerations because of a better understanding of utilization and care patterns for NHL.
2014 to 2018 were all inflated to a common 2019 dollar value using the medical care component of the Consumer Price Index available at the Bureau of Labor Statistics. 19

COVARIATES
All independent variables regarding the demographic or socioeconomic status of patients were defined based on the self-reported information available on the HC, including age, race and ethnicity, marital status, educational level, income level, and insurance status. In addition, the Elixhauser comorbidity score, a well-known tool providing a valid comorbidity score representative of the patient's comorbidity burden, was used. To avoid double consideration of the cancer diagnosis among our study population, 3 of 31 health conditions included in the Elixhauser scale were removed, namely lymphoma, metastatic cancer, and solid tumor without metastasis. Further, because of the limitation of MPC in distinguishing similar health conditions (3 characters rather than 5 characters for the International Classification of Diseases, Ninth and Tenth Revisions), 2 pairs of conditions were merged (blood-loss/deficiency anemia and uncomplicated/complicated hypertension), leading to a modified Elixhauser scale with 26 comorbidities. 20 Elixhauser comorbidity scores were dummy coded and used as a categorical variable. 21 Based on the number of comorbidities identified from the medical component, patients were categorized into 0, 1, 2, and 3 comorbidity categories.

STATISTICAL ANALYSIS
Descriptive weighted analyses were used to compare the characteristics of patients with NHL and other cancers. To analyze the incremental total health care expenditure of NHL after adjusting for the covariates, we used a 2-part model (TPM), allowing for mixed discrete-continuous dependent variables. 22 The TPM is a commonly used method for health care expenditure analysis that provides precise estimates and addresses issues such as positive skewness as well as excessive zero expenditures. The TPM uses estimates from both parts of the model for the calculation of incremental effects and SEs. 15,22,23 In the first part, a probit model estimated the probability of having a nonzero vs having a zero health care expenditure. In the second part, conditional on having a nonzero expenditure, a generalized linear model (GLM) was used to estimate the incremental total health care expenditure of NHL vs other cancers. Using a modified Park test, the current study sample was determined to have a Poisson family distribution. Further, a Pregibon link test was used to find the most appropriate link function for the second part. After verification of the most appropriate family demographic characteristics, educational level, income level, insurance coverage, and health care utilization. The HC data include comprehensive information on expenditures from various health care components, including prescriptions and inpatient care. 12,14 In addition, the HC was used for the identification of patients diagnosed with NHL or other cancers. The MPC is an event-level dataset collected from health care providers regarding the health condition of individuals who participated in the HC. The MPC provides additional accurate medical information for HC respondents, including diagnosis, dates of visits/ services, medical care services used, charges, payment sources/amounts, and procedure codes for medical visits/ encounters. Data from 6 years (2014-2019) of HC and MPC files were pooled to analyze the incremental health care expenditures in individuals with NHL in comparison with other cancers. Next, a pooled linkage file for the common variance structure provided by the Agency for Healthcare Research and Quality was included for pooled analysis by merging the variables STRA9619 (stratum) and PSU9619 (primary sampling unit) from the HC-036 file. 16 These survey design variables involving stratum and primary sampling units were incorporated in the pooled statistical analyses along with the sampling weights adjusting for multiple years to derive the annual estimates. The study was approved by the institutional review board at the University of Houston.

STUDY SAMPLE AND OPERATIONAL DEFINITION
The study sample included all individuals aged at least 18 years who were diagnosed with NHL between 2014 and 2019. The comparison group comprised all individuals older than 18 years who had a cancer diagnosis other than NHL during the same period. Identification of individuals was based on 2 variables on the HC, namely CANCERDX (cancer diagnosis) and CALYMPH (lymphoma diagnosis). 17 There is another health condition called Hodgkin lymphoma that is not considered as a cancer but could have been identified under the umbrella of a lymphoma diagnosis. Therefore, we excluded the patients who were diagnosed with lymphoma but did not have a recorded cancer diagnosis (n = 2).

HEALTH CARE EXPENDITURE
Expenditure estimates on the HC were the paid amount for all health services received (either by patients or payers) and not the cost of the services to the providers. Total health care expenditures were the aggregate expenditures on hospitalization, outpatient care, emergency department, prescribed medications, dental care, vision, home health care, and other medical services, including ambulance, glasses, and other equipment. 12

INCREMENTAL HEALTH CARE EXPENDITURES
After adjusting for all covariates, the total health care expenditure of patients with NHL was $7,283.58 (95% CI = $1,432.28-$13,134.89) higher than that for patients with other cancers (Table 3). In addition, the total expenditure, excluding prescription medications, was $6,349.19 (95% CI = $1,138.58-$11,559.79) higher for the NHL group compared with that for the other cancers group (Table 4). Furthermore, the adjusted incremental expenditure regarding office-based visits for the NHL group was $2,640.85 (95% CI = $1,128.80-$4,152.90) ( Table 4). The adjusted hospital inpatient care (35.37%) and office-based visits (36.26%) costs accounted for 71.63% of the adjusted total health care expenditures (Table 4).

SENSITIVITY ANALYSIS
Modeling the expenditures based on gamma family distribution provided consistent findings with the main analyses. The NHL group still had a $5,816.92 (95% CI = $1,171.24-$10,462.61) higher expenditure compared with that of the other cancers group. In addition, the office-based expenditure, modeled based on gamma family distribution, revealed a $2,506.83 (95% CI = $1,031.23-$3,982.43) higher expenditure for NHL in comparison with other cancers.

Discussion
This is the first study evaluating the incremental health care expenditure among patients with NHL compared with all other cancer populations, thus providing insight distribution and the link function for the study population, the best GLM model with a log link function was selected.
The variance inflation factor was also calculated to rule out multicollinearity. For the sensitivity analysis, incremental expenditures were computed using a different family distribution (gamma vs Poisson) in the second part of the TPM. We chose the gamma family distribution for comparison because the gamma distribution is the model most utilized for modeling health care expenditures. Because of the multistage probability design of the MEPS data collection, all the data analyses were adjusted using the cluster, strata, and weight variables. Adjusting the analysis provided nationally representative estimates and SEs. All statistical analyses were carried out using SAS 9.4 (SAS Institute), whereas Stata/MP 17 (StataCorp) was used for fitting the TPM for finding the NHL incremental expenditures compared with all other cancers. One of the main advantages of using TPM is that the model provides estimates of marginal expenditures after incorporating the appropriate retransformation from the estimation scales in the GLM in the second part. 22

PATIENT CHARACTERISTICS
This study included 370 unweighted patients diagnosed with NHL representing an annual nationwide weighted estimate of 740,677 patients with NHL (95% CI = 621,963-859,390), accounting for 2.59% of all patients diagnosed with cancer in the United States during the study period. The comparative group, including all patients with a cancer diagnosis other than NHL, were 13,923 unweighted individuals representing 27,909,027 (95% CI = 26,702,190-29,115,863) patients annually. The NHL group was younger than the other cancers group with a mean age of 60.62 (SD = 1.16) years compared with 65.42 (SD = 0.21) years for the other cancers groups (P < 0.05). The mean scores for the modified Elixhauser comorbidity scale were similar for both the NHL (mean = 0.74; 95% CI = 0.67-0.80) and the other cancers (mean = 0.80; 95% CI = 0.78-0.81) groups. More details about the sample characteristics are available in Table 1.
The most common comorbidity among both groups was hypertension, with a prevalence of 37.12% among patients with NHL and 41.59% among those in the other cancers group. The second prevalent comorbidity among both groups was depression, with a prevalence of 7.16% and 7.79% among the NHL and other cancers groups, respectively. care (29%), office-based visits (28%), and prescription medications (19%).
Previous literature reported the total health care expenditures were higher than our finding ($21,698/year). 24  . This finding provides more evidence that similar to the most common cancers (including breast, prostate, lung, and colorectal), office-based visits are the largest part of cancer care. 27 However, our finding was slightly different from a previous study regarding the distribution of expenditures for office-based visits and hospital inpatient services. 5 Kuticova et al found that, depending on the severity of the disease among patients with NHL, 46%-52% of the health care expenditure was spent on hospital care, and 33%-38% was spent on outpatient office visits. The small difference in the findings of our study can be explained by considering the time that studies were conducted. The study by Kuticova et al was carried out using data from 1999 to 2000, which is at least 14 years older than the data used in our study. Careful consideration of the findings suggests that after 2000, a noticeable portion of care previously received in hospital inpatient settings was shifted to outpatient and office-based visits. 28 This transition in the facilities providing care for patients with NHL can also explain the lower total cost observed in our study compared with previous studies. 5,24,25 On the other hand, the study by Kuticova et al was specifically focused on the first 2 years after NHL diagnosis, which provides limited generalizability to the survivorship years after NHL with possibly lower economic burden and a different pattern of health care utilization. 5 The total health care expenditure for NHL was higher than the other cancers. Although the incremental differences for several components of the health care can be explained by 2 important differences between the studies. 24 First, Shah et al used Medicare data, indicating that their study sample was older (mean = 75.15 years; SD = 6.9) than our study (mean = 60.62 years; SD = 1.16). On the other hand, the study population in the Shah study was followed for the first 2 years after the diagnosis, which is probably the costliest period of the disease, whereas, in our study, NHL annual health care expenses were evaluated for newly diagnosed and prevalent patients irrespective of the diagnosis date. 24 Another study by Morrison et al evaluated the economic burden of 2 of the most common types of NHL, namely diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). They reported all-cause monthly costs of $11,890 for DLBCL and $10,460 for FL. 26 Careful consideration of this study showed that higher estimates might be explained by 2 factors. First, the average age of the study population in the study by Morrison et al (mean = 68 years) was higher. Second, their study was limited to the first 2 years after the diagnosis, which is the costliest period of the disease, as they reported an average monthly cost of $14,402 for patients with DLBCL, followed by a dramatically lower cost during the second year (mean = $4,190). A similar trend was seen in the patients with FL, with a monthly cost of $12,183 during the first year after diagnosis, followed by an average monthly cost of $5,062 during the second year after diagnosis. 26 We found that the majority of the difference between our comparison groups was attributable to office-based visits (36.26% of the total) and hospital inpatient services

LIMITATIONS
Despite these strengths, our study had certain limitations. There were some limitations due to the utilization of the MEPS, including a lack of information about institutionalized individuals and patients in nursing homes. Also, the coding limitations of MEPS (3 digits vs 5 digits) necessitated making some modifications in our comorbidity scale that might have resulted in overestimating or underestimating patients' comorbidities. Further, health care cost differs among patients with NHL depending on the NHL type, stage, and grade of cancer. However, because of the MEPS limitations in providing information about the disease, our study did not adjust for the disease severity. Similarly, because information about the cost of different treatments was not provided, our estimate was focused on the overall annual expenditure. Lastly, the survey-based MEPS data were prone to underreporting or overreporting because of the recall bias of household respondents.

Conclusions
NHL is a chronic disease with a larger economic burden in comparison with other cancers. Our national study indicated that the magnitude of economic burden among patients The other factor contributing to the higher utilization of health care services, and particularly office-based visits, is the high chance of recurrence among patients with NHL. During the first year after the treatment initiation, 50% of patients with NHL experience a recurrence, whereas the annual recurrence rate for breast cancer is about 2% and for prostate cancer it is about 15%. 30-32 Studies have shown that the majority of recurrences (83%) are suspected during a history, and physical examination and 17% of recurrences are identified by routine follow-up imaging or laboratory tests. 30 Early detection of disease recurrence among patients with NHL necessitates more frequent physical examinations followed by required modifications in treatment. Finally, because of the high chance of disease transformation among patients with NHL, frequent lymph node biopsies are required for the identification of more aggressive subtypes of the disease. Autopsy results have shown that half of the patients who died from NHL had evidence indicating the transformation of the disease. 30 Frequent lymph node biopsies result in the earlier detection of transformations and the ability to adjust treatment. Overall, the study findings can benefit managed care organizations and payers by understanding the economic burden of NHL to assist in value-based care considerations. Our study had 4 major strengths that make it stand out among other studies. First, we used a nationally representative sample from the MEPS for the first time to evaluate the economic burden of NHL among the US population. Second, we conducted a TPM for our analysis, which is a robust method for handling expenditures with specific